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更新于：2025-05-07

CXXC5

更新于：2025-05-07

基本信息

别名

CF5、CXXC finger protein 5、CXXC-type zinc finger protein 5

+ [7]

简介

May indirectly participate in activation of the NF-kappa-B and MAPK pathways. Acts as a mediator of BMP4-mediated modulation of canonical Wnt signaling activity in neural stem cells (By similarity). Required for DNA damage-induced ATM phosphorylation, p53 activation and cell cycle arrest. Involved in myelopoiesis. Transcription factor. Binds to the oxygen responsive element of COX4I2 and represses its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen) (PubMed:23303788). May repress COX4I2 transactivation induced by CHCHD2 and RBPJ (PubMed:23303788). Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (PubMed:29276034).

关联

项与 CXXC5 相关的药物

KY19334

靶点

CXXC5

作用机制

CXXC5 modulators

在研机构

CK Regeon Inc.

原研机构

CK Regeon Inc.

在研适应症

非酒精性脂肪性肝炎 [+3]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Wound healing(CK Regeon)

靶点

CXXC5

作用机制

CXXC5 inhibitors

在研机构

CK Regeon Inc.

原研机构

CK Regeon Inc.

在研适应症

创伤和损伤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CXXC5 相关的临床结果

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100 项与 CXXC5 相关的转化医学

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0 项与 CXXC5 相关的专利（医药）

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169

项与 CXXC5 相关的文献（医药）

2025-03-01·Bioorganic Chemistry

Targeting Wnt signaling pathway with small-molecule therapeutics for treating osteoporosis

Review

作者: Hussain, Mohd Kamil ; Ahamad, Shakir ; Saquib, Mohammad ; Bhat, Shahnawaz Ali

Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge. Despite advancements in computer-aided drug design, it is rarely employed for designing Wnt signaling activators to treat osteoporosis, and high-throughput screen (HTS) remains the primary method for discovering initial hits. Acknowledging the promising therapeutic potential of these compounds in addressing bone diseases, this review underscores the need for further mechanistic elucidation to enhance our understanding of their applications. Additionally, caution must be exercised in the design of small molecule-based Wnt activators due to their association with oncological risks.

2025-03-01·Gene

Novel oncogenes and tumor suppressor genes in Hepatocellular Carcinoma: Carcinogenesis, progression, and therapeutic targets

Review

作者: Shamsinejad, Fatemeh Sadat ; Shahbazi, Taha ; Bolideei, Mansoor ; Rahimi-Farsi, Nasim ; Boustani, Farnaz ; Zangooie, Alireza ; Shoorei, Hamed ; Bostanian, Fatemeh ; Mohseni, Parvin

Hepatocellular carcinoma (HCC) is the primary malignancy affecting the liver and the leading cause of mortality among individuals with cirrhosis. This complex disease is associated with various risk factors, including environmental, pathological, and genetic influences, which dysregulate gene expression crucial for the cell cycle and cellular/molecular pathways. The disruption of the balance between tumor suppressors and proto-oncogenes amplifies the pathogenic cascade. Given its predilection for diseased or cirrhotic livers and late-stage diagnosis, HCC prognosis is typically poor. Current therapies offer limited benefits, with conventional non-specific cytotoxic agents exhibiting suboptimal efficacy. However, molecularly targeted therapies have emerged as a promising avenue, leveraging the strategic inhibition of carcinogenic molecules to provide heightened specificity and potency compared to cytotoxic chemotherapy. Several clinical trials have demonstrated promising outcomes in advanced HCC with targeted pharmacotherapies. Many genes have been implicated in HCC pathogenesis, underscoring the need to elucidate their molecular functions and roles. This has profound implications for early HCC prognostication via biomarkers and for identifying therapeutic targets to impede neoplastic progression. Notably, evidence highlights the pivotal roles of oncogenes and tumor suppressors in HCC pathophysiology. This discourse examines the potential involvement of ABL1, Annexins, FAK, FOX, and KIF as candidate oncogenes, contrasted with SORBS2, HPCAL1, PCDH10, PLAC8, and CXXC5 as plausible tumor suppressors. Their signaling cascades and relevance to HCC prognosis and progression are delineated to identify targets for improving HCC diagnosis, prognostication, and therapy.

2024-12-01·Biochemical Pharmacology

Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis

Review

作者: Chand, Diwan ; Mohanan, Kishor ; Chattopadhyay, Naibedya ; Ahamad, Shakir ; Srivastava, Kinshuk R ; Abhishek Shah, Aarti ; Chourasia, Manish K ; Srivastava, Kinshuk R. ; Porwal, Konica ; Chourasia, Manish K.

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.

项与 CXXC5 相关的新闻（医药）

2022-08-02

·生物谷

Nature子刊：郗乔然/张力伟合作揭示BMP信号通路在脑胶质瘤中的抑癌作用

系统性地阐述了BMP信号通路在ACVR1野生型，H3.3K27M突变型弥漫内生型脑桥胶质瘤中的抑癌作用。弥漫内生型脑桥胶质瘤（Diffuse Intrinsic Pontine Glioma，DIPG）是一种位于脑桥区域不易手术切除、无有效治疗手段的中枢神经系统恶性肿瘤。该类肿瘤高发于儿童，两年生存率小于10%，对患儿家庭和社会造成极大的心理伤害和经济负担。在大约80%的DIPG中，DIPG肿瘤发生的驱动因素来自组蛋白H3.1K27M和H3.3K27M突变。其中H3.3K27M突变病人预后最差，而H3.1K27M 突变病人有更长的生存期，两个DIPG亚群有着不同的致病机理和临床特征，所以分别研究这两个DIPG亚群的致病机制和潜在的治疗策略势在必行。骨形态发育蛋白（Bone Morphogenetic Protein，BMP）信号通路会根据肿瘤细胞环境行使其抑制或促进肿瘤的作用。造成BMP信号通路自激活的ACVR1突变与H3.1K27M突变共同促进约20%的DIPG亚群肿瘤的发展，但BMP信号通路对占比60%的ACVR1野生型，H3.3K27M突变型DIPG亚群的影响仍是未知。 2022年8月1日，清华大学生命科学学院郗乔然课题组和首都医科大学附属北京天坛医院张力伟课题组合作，在 Nature 子刊 Nature Cancer 上在线发表了题为：Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5 （BMP信号通路在弥漫内生型脑桥胶质瘤中的抑癌作用）的研究论文。研究团队系统性地阐述了BMP信号通路在ACVR1野生型，H3.3K27M突变型弥漫内生型脑桥胶质瘤中的抑癌作用。在这项研究中，研究团队首次系统性地研究了BMP信号通路在ACVR1野生型，H3.3K27M突变型弥漫内生型脑桥胶质瘤中的抑癌作用。首先，研究团队从现有的对此DIPG亚群的转录组分析中发现相对于正常脑桥祖细胞及正常脑桥组织，这一亚群DIPG细胞和组织都具有一致性相对低的BMP信号通路活性。接下来，研究团队利用未经放化疗治疗的病人来源的DIPG细胞系作为研究材料，通过生物信息学分析和实验验证相结合的方式，发现了ACVR1野生型，H3.3K27M突变型DIPG中高表达的BMP信号通路的拮抗因子CHRDL1是造成其中BMP信号通路异常下调的原因。高表达CHRDL1不仅和DIPG病人的不良预后正相关，而且实验证明CHRDL1是DIPG的促癌因子。进而，研究团队展示了重新激活此DIPG亚群中BMP信号通路会通过SMADs发挥对DIPG体外和体内生长的抑癌作用。进一步，研究团队通过转录组和表观遗传组分析探究了BMP信号通路在此DIPG亚群中发挥抑癌作用的分子机制：激活BMP信号通路驱使此DIPG亚群退出干细胞状态，促进细胞分化，引起细胞周期停滞和细胞凋亡。并且，研究团队鉴定出BMP信号通路通过表观遗传调控下游靶基因CXXC5发挥抑癌作用。最后，通过药物筛选的方法，研究团队找到了可以激活此DIPG亚群中BMP信号通路并可能作为治疗DIPG的小分子药物——Dacinostat。 BMP信号通路抑制H3.3K27M ACVR1 WT DIPG模式图清华大学生命学院郗乔然副教授、首都医科大学附属北京天坛医院张力伟教授为论文共同通讯作者，清华大学博士生孙晔、闫坤、以及首都医科大学附属北京天坛医院王一和徐骋为共同第一作者。上海交通大学唐玉杰课题组及清华大学生命科学学院张强锋课题组对本研究的顺利开展做出了重要贡献。

小分子药物合作